Chen, Lu Download PDFPatent Trials and Appeals BoardMay 21, 20202019003234 (P.T.A.B. May. 21, 2020) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/004,646 01/22/2016 Lu Chen BERK-236 (BK-2012-101-3) 8240 84220 7590 05/21/2020 UC BERKELEY - OTL BOZICEVIC, FIELD & FRANCIS LLP 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER HADDAD, MAHER M ART UNIT PAPER NUMBER 1644 NOTIFICATION DATE DELIVERY MODE 05/21/2020 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte LU CHEN ____________ Appeal 2019-003234 Application 15/004,646 Technology Center 1600 ____________ Before ERIC B. GRIMES, ULRIKE W. JENKS, and MICHAEL A. VALEK, Administrative Patent Judges. VALEK, Administrative Patent Judge. DECISION ON APPEAL Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving claims to a method of treating corneal transplant rejection that have been rejected for lack of written description under 35 U.S.C. § 112(a) and for obviousness under 35 U.S.C. § 103. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies The Regents of the University of California as the real party in interest. Appeal Br. 3. Appeal 2019-003234 Application 15/004,646 2 STATEMENT OF THE CASE The Specification states that “[l]ymphangiogenesis (LG) is involved in a number of diseases” and is related to “immune-mediated rejection” of tissue transplants. Spec. 1:20–22. According to the Specification, Methods of modulating the occurrence of lymphangiogenesis in a subject are provided. In some instances, the method includes reducing antigen presenting cell function, such as cell trafficking to draining lymph nodes. In some instances, the method includes treating corneal transplant rejection in the subject. Aspects of the methods include administering to the subject an effective amount of an antagonist of angiopoietin-2 (Ang-2) to reduce the occurrence of lymphangiogenesis. Id. at 2:1–7. Claims 44–46, 50–52, and 56 are on appeal and can be found in the Claims Appendix of the Appeal Brief. Claim 44 is representative and reads as follows: 44. A method of treating corneal transplant rejection in a subject, the method comprising: administering to a subject in need thereof an effective amount of an Ang-2 neutralizing antibody to antagonize the Ang-2 ligand at the Tie-2 receptor to treat the subject for corneal transplant rejection; and transplanting corneal tissue in a graft bed of the subject. Appeal Br. 33. Appellant does not argue the claims separately. We focus our analysis on claim 44. Claims 45, 46, 50–52, and 56 stand or fall with that claim. 37 C.F.R. § 41.37(c)(1)(iv). Appellant seeks review of the following rejections: I. Claims 44–46, 50–52, and 56 under 35 U.S.C. § 112(a), for failure to meet the written description requirement (“Written Description Rejection”); Appeal 2019-003234 Application 15/004,646 3 II. Claims 44–46, 50–52, and 56 under 35 U.S.C. § 103 as unpatentable over Dietrich,2 Chen,3 Holopainen,4 and Bzowska5 (“Rejection II”); III. Claim 44–46, 50–52, and 56 under 35 U.S.C. § 103 as unpatentable over Cursiefen6 or Bachmann7 and Cao8 (“Rejection III”); and IV. Claims 44–46, 50–52, and 56 under 35 U.S.C. § 103 as unpatentable over Cursiefen or Bachmann and Bzowska (“Rejection IV”). Appeal Br. 3–4. 2 Tina Dietrich et al., Cutting Edge: Lymphatic Vessels, Not Blood Vessels, Primarily Mediate Immune Rejections After Transplantation, 184 J. Immunology 535–39 (2010) (“Dietrich”). 3 Lu Chen et al., Specific Role of Angiopoietin-2 in Corneal Lymphangiogenesis, ARVO Annual Meeting Abstr. (May 2011) (“Chen”). 4 Tanja Holopainen et al., Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell-Cell Junctions and Lung Metastasis, 104 J. Nat’l Cancer Inst. 461–75 (2012) (“Holopainen”). 5 Monika Bzowska et al., Antibody-based Antiangiogenic and Antilymphangiogenic Therapies to Prevent Tumor Growth and Progression, 60 Acta Biochem Pol. 263–75 (2013) (“Bzowska”). 6 Claus Cursiefen et al., Inhibition of Hemangiogenesis and Lymphangiogenesis After Normal-Risk Corneal Transplantation by Neutralizing VEGF Promotes Graft Survival, 45 Invest Ophthalmol Vis Sci. 2666–73 (2004) (“Cursiefen”). 7 Bjoern O. Bachmann et al., Promotion of Graft Survival by Vascular Endothelial Growth Factor A Neutralization After High-risk Corneal Transplantation, 126 Arch Ophthalmol. 71–77 (2008) (“Bachmann”). 8 Jingtai Cao et al., Neutralization of Angiopoietin-2 Inhibits Ocular Angiogenesis and Vascular Leak, and Promotes Regression of Choroidal Neovascularization, ARVO Annual Meeting Abstr. (May 2011) (“Cao”). Appeal 2019-003234 Application 15/004,646 4 I. WRITTEN DESCRIPTION REJECTION Issue The issue for this rejection is whether a preponderance of the evidence supports Examiner’s finding that claims 44–46, 50–52, and 56 fail to comply with the written description requirement. Analysis Examiner determines the written description requirement is not met because [t]he specification does not describe the complete structure of conventional Ang-2 antagonist antibodies that treat corneal transplant rejection or reducing the occurrence of lymphagiogenesis [sic] in a skin tissue of a skin transplantation. Further, the specification does not describe the partial structures, or physical properties, or chemical properties of conventional Ang-2 antagonist antibodies that would reduce the occurrence of lymphagiogenesis [sic] in a skin tissue or corneal tissue. Final Act. 4–5. According to Examiner, “None of the prior art anti-Ang-2 antibodies disclose[d] in the prior art has the claimed therapeutic function and functional properties such as inhibiting lymph[]atic vessel growth but does not significantly inhibit blood vessel growth.” Id. at 7. Appellant disputes Examiner’s rejection, arguing that “the claimed method does not require the use of an unconventional Ang-2 antagonist antibody that is distinct from the exemplary anti-Ang-2 antibodies of the present specification and the prior art, which block binding of Ang-2 ligand to its cognate receptor Tie-2.” Appeal Br. 7. According to Appellant, the “sequences and structures of a variety of Ang-2 neutralizing antibodies that antagonize the Ang-2 ligand at the Tie-2 receptor were known” and the Appeal 2019-003234 Application 15/004,646 5 “specification describes a representative number of Ang-2-binding antibodies from the art which may be used as an Ang-2 neutralizing antibody in the claimed method.” Id. at 8 (citing Spec. 16:15–22). We determine that Appellant has the better argument. Claim 44 recites administering “an effective amount of an Ang-2 neutralizing antibody to antagonize the Ang-2 ligand at the Tie-2 receptor to treat the subject for corneal transplant rejection.” The Specification identifies a number “[s]pecific examples of antibody agents that can be employed as [the] Ang-2 antagonist” in this method and includes citations to references demonstrating that such antibodies were known in the art. Spec. 16, ll. 15–22. Moreover, Appellant cites additional references demonstrating that a skilled artisan would have been aware of both the structure of the exemplary anti-Ang-2 antibodies in the Specification, including their CDR sequences, and their function in preventing binding of Ang-2 to its cognate Tie-2 receptor. Id. at 9–10. Thus, we agree with Appellant that the Specification describes a representative number of species for use in the method of claim 44. Examiner’s rejection is premised on an incorrect interpretation of Appellant’s claims, i.e., that the claimed method requires an antibody that inhibits lymphangiogenesis (LG) without “significantly inhibit[ing] blood vessel growth.” See Final Act. at 7. Claim 44, however, does not recite an antibody that selectively inhibits LG over hemangiogenesis (HG) or otherwise acts without inhibiting blood vessel growth.9 The Specification 9 Examiner incorrectly quotes claim 44 as reciting “an amount of an Ang-2 antagonist effective to selectively inhibit lymphatic vessel growth relative to blood vessel growth.” Final Act. 3. The claims, however, were subsequently amended to delete this language. See Response After Final Action filed May 29, 2018. No such language currently appears in claim 44 Appeal 2019-003234 Application 15/004,646 6 states that “[p]racticing the subject method can result in selective inhibition of the growth of lymphatic vessels of interest relative to the growth of blood vessels of interest,” but it does not indicate that selective inhibition is required to treat corneal transplant rejection. See Spec. 11:3–23 (emphasis added). Thus, given its broadest reasonable interpretation, all claim 44 requires is the administration of an antibody that antagonizes the Ang-2 ligand at the Tie-2 receptor in an amount effective to treat the subject for corneal transplant rejection. The Specification states that any of the exemplary antibodies it identifies are useful for this purpose. See Spec. 16, ll. 15–22. Examiner cites no evidence to the contrary. Thus, the record does not support Examiner’s finding that “[n]one of the anti-Ang-2 antibodies taught in the prior art [and described in the Specification] have the claimed therapeutic function, specificity and functional attributes.” Final Act. 7. For this reason, the Written Description Rejection is not supported by the preponderance of the evidence. We, therefore, reverse that rejection. II. OBVIOUSNESS REJECTION OVER DIETRICH, CHEN, HOLOPAINEN, AND BZOWSKA Issue The issue for this rejection is whether the preponderance of evidence of record supports Examiner’s conclusion that the combination of Dietrich, Chen, Holopainen, and Bzowska renders Appellant’s claimed method obvious. Findings of Fact or any of the dependent claims on appeal here. Appeal 2019-003234 Application 15/004,646 7 FF1. Dietrich describes a study “to determine the relative importance of blood vessels (hemangiogenesis) versus lymphatic vessels (lymphangiogenesis) in mediating immunological responses after transplantation.” Dietrich, 535. The authors used a “murine model of corneal transplantation” and administered “antivascular endothelial growth factor receptor 3 [VEGFR3] Abs and anti-integrin α5 small molecules” to selectively inhibit LG prior to transplantation of donor corneas into “avascular, prehemvascularized only or prehemvascularized and prelymphvascularized recipient murine eyes.” Id. FF2. Dietrich reports that when LG was selectively inhibited, “[g]rafts placed into only prehemvascularized recipient beds had a similarly good graft survival compared with grafts placed into completely avascular, normal recipients, whereas the pre-existence of lymphatic vessels significantly deteriorated corneal graft survival.” Dietrich, 535. According to Dietrich, these findings “suggest that corneal lymphatic vessels promoting sensitization are the most important mediator of immune rejections after corneal transplantation.” Id. at 538. FF3. Dietrich also teaches that “combined modulation of hemangiogenesis and lymphangiogenesis by vascular endothelial growth factor (VEGF)-Trap after normal-risk corneal transplantation improved graft survival in the murine model of corneal transplantation.” Id.; see also id. at 537 (Fig. 2 (red line)). FF4. Dietrich teaches that “corneal transplantation can experimentally serve as a model for allogenic transplantation, which allows for the analysis of the impact of lymphatic and blood vessels on the graft outcome, because of the cornea’s normal avascularity.” Dietrich, 535. Dietrich explains that Appeal 2019-003234 Application 15/004,646 8 “the normally avascular cornea” enjoys an “immune privilege” resulting in a lower rate of immune rejection in patients with avascular graft beds as compared to high risk patients with prevascularized or inflamed beds. Id. Dietrich further teaches that “[i]n contrast to the avascular cornea, solid organ grafting requires a blood supply to provide wound healing and nutrition.” Id. at 538 (referring to heart and renal transplant as examples of solid organ grafting). FF5. Chen describes experiments to “investigate[] whether angiopoietin-2 (Ang2) is involved in corneal inflammatory lymphangiogenesis (LG).” Chen, 1. The authors used “murine suture-induced corneal inflammation and human lymphatic endothelial cell (LEC) cultural models . . . to study the expression of Ang2 on newly formed lymphatic vessels” and also assessed “corneal inflammatory LG . . . in Ang2 knockout” mice. Id. Chen reports that “Ang2 expression was detected on both newly formed lymphatic vessels in the cornea and LECs in culture” and that “corneal LG was significantly suppressed in Ang2 knockout mice.” Id. Chen teaches that “[t]hese new findings indicate that the Ang2 pathway is critically involved in lymphatic processes” and may provide novel strategies to address lymphatic disorders “such as corneal transplant rejection.” Id. FF6. Holopainen describes experiments exploring “the effect of Ang2 on tumor progression and metastasis” involving injection of the Ang2-blocking antibody, MEDI3617, into various animal models. Holopainen, 461. Holopainen teaches that “Ang2-blocking antibodies inhibit primary tumor growth, angiogenesis, and lymphangiogenesis.” Id. at 467 (Fig. 3). FF7. Bzowska teaches that “[e]xcessive lymphangiogenesis is observed in” a number of conditions including “graft rejection” and tumor progression. Appeal 2019-003234 Application 15/004,646 9 Bzowska, 267. Bzowska discloses a number of “monoclonal antibodies as inhibitors of lymph- and angiogenesis,” including VEGFR3 antibodies as well as the Ang-2 antibodies, LC06 and MEDI3617. Id. at 264 (Table 1). Bzowska teaches that these Ang-2 antibodies prevent Ang-2 binding to the Tie2 receptor and exhibit “antiangiogenic action.” Id. Analysis We agree that claim 44 is obvious over the combination of Dietrich, Chen, Holopainen, and Bzowska. Specifically, Dietrich teaches that selective inhibition of LG as well as the combined inhibition of both LG and HG improve corneal graft survival. FF1–FF3. Chen teaches that Ang-2 is “critically involved” in corneal inflammatory LG processes and reasonably suggests targeting Ang-2 as a strategy to treat corneal transplant rejection. FF5. Holopainen and Bzowska teach Ang-2 neutralizing antibodies that “antagonize the Ang-2 ligand at the Tie-2 receptor,” as recited in claim 1, to inhibit both LG and angiogenesis. FF6–FF7. In light of these teachings, we agree with Examiner’s conclusion that it would have been obvious to a skilled artisan to administer the Ang-2 neutralizing antibodies taught in Holopainen and Bzowska in the methods of treating corneal transplant rejection taught in Dietrich. See Final Act. 16–17. One of skill in the art would have been motivated to make this modification and have had a reasonable expectation of success in doing so in light of the teachings in Chen noted above. See FF5. We are not persuaded by Appellant’s argument that “Dietrich fails to teach a method directed to dual inhibition of both hem- and lymph- angiogenesis” and, therefore, a “skilled artisan would not modify Dietrich’s method, without guidance that an Ang-2 antibody selectively inhibits Appeal 2019-003234 Application 15/004,646 10 undesirable LG without affecting desirable HG in a relevant context.” See Appeal Br. 17–19. As an initial matter, the premise for Appellant’s argument is incorrect. Dietrich, in fact, teaches that combined inhibition of LG and HG is effective to improve corneal graft survival. FF3. In addition, Appellant’s reliance on Dietrich’s teaching that “blood supply is essential for healing in transplantation (page 6, last paragraph 3)” is misplaced. Appeal Br. 17. The same paragraph Appellant cites expressly distinguishes cornea tissue from transplantation of “solid organs.” See Dietrich, 538 (“In contrast to the avascular cornea, solid organ grafting requires a blood supply to provide wound healing and nutrition.”) (emphasis added). In fact, Dietrich suggests that HG is not necessary for cornea transplantation (FF4) and that inhibition of such along with LG will improve corneal graft survival (FF3). Thus, Dietrich does not support Appellant’s argument that a skilled artisan would be discouraged from administering Ang-2 neutralizing antibody in corneal transplants because it was known that such antibodies inhibit both LG and HG. See Appeal Br. 18. We are likewise unpersuaded by Appellant’s argument that Examples 1 and 2 of the Specification demonstrate “unexpected results . . . sufficient to overcome” the prima facie showing of obviousness. Appeal Br. 19–21. Example 1 shows results from various experiments involving Ang-2 knockout mice and downregulation of Ang-2 expression “by a siRNA- mediated gene silencing approach.” Spec. 59–61. The results in Example 1 are not persuasive evidence of non-obviousness for several reasons. First, Appellant has not demonstrated a sufficient nexus between the techniques used in Example 1, which do not involve administration of an Ang-2 neutralizing antibody, and the claimed method. See In re Huai-Hung Kao, Appeal 2019-003234 Application 15/004,646 11 639 F.3d 1057, 1068–69 (Fed. Cir. 2011) (explaining that for evidence of unexpected results “to be accorded substantial weight, its proponent must establish a nexus between the evidence and the merits of the claimed invention”) (quotations omitted). Second, the results showing increased Ang-2 expression “in inflamed mouse cornea using the suture placement model” and abolished corneal LG response in Ang-2 knockout mice (see Spec. 59–60) were disclosed in Chen. FF5. While Example 1 appears to include some additional experiments not disclosed in Chen, the Specification draws the same conclusions regarding those experiments as was already taught Chen. Compare Spec. 53, ll. 26–28 (“Angiopoietin-2 is critically involved in lymphatic processes in vivo and in vitro in different tissues and sites. Modulation of the Ang-2 pathway can provide therapeutic strategies for lymphatic-related disorders, which occur both inside and outside the eye.”), with Chen, 1. Accordingly, Appellant has not shown that the results in Example 1 would have been unexpected in view of Chen. Likewise, Specification Example 2 does not demonstrate persuasive evidence of unexpected results. According to Example 2, administration of an anti-Ang-2 antibody purchased from Eli Lilly in “[t]ransplantation experiments . . . performed in normal mouse corneas (i.e., low risk of transplant rejection)” was effective to suppress “transplantation-induced corneal lymphangiogenesis and donor derived cell trafficking (i.e., antigen presenting cell trafficking) to draining lymph nodes after transplantation and promotes corneal graft survival.” Id. However, such results would have been expected from the prior art teachings showing that: (1) LG is the most important mediator of corneal transplant rejection (FF2), (2) suppression of Ang-2 in Ang-2 knockout mice significantly suppressed corneal LG (FF5), Appeal 2019-003234 Application 15/004,646 12 and (3) anti-Ang-2 antibodies were known to suppress both LG and HG in other contexts (FF6–7). See In re Gershon, 372 F.2d 535, 537 (CCPA 1967) (“Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected beneficial results are evidence of unobviousness thereof.”). In addition, the record does not demonstrate that the results in Example 2 are “different in kind and not merely in degree” from what would be expected from the prior art. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 739 (Fed. Cir. 2013) (“Unexpected results that are probative of nonobviousness are those that are different in kind and not merely in degree from the results of the prior art.”) (quotations omitted). To the contrary, the degree of increased graft survival that Appellant observed in Example 2 appears to be similar to that reported for VEGF-Trap treatment (to inhibit both LG and HG) in Dietrich. Compare Spec. Fig. 6C, with Dietrich, 537 (Fig. 2a (red line)). Appellant acknowledges that “Holopainen and Bzowska disclose Ang-2 inhibition as both anti-angiogenic (HG) and anti- lymphangiogenic (LG) therapy.” Appeal Br. 18–19. Thus, Appellant has not shown how the results in Example 2 differ in kind from the results a skilled artisan would expect from the substituting the anti-HG and anti-LG therapy in Dietrich (i.e., VEGF-A Trap) with that taught in Holopainen and Bzowska (i.e., Ang-2 neutralizing antibody). For these reasons, when considered in context of the record as a whole, Appellant’s evidence does not overcome the prima facie showing of obviousness. Thus, we determine that the preponderance of the evidence supports Examiner’s rejection. We recognize, however, that the rationale Examiner offers in support of the rejection (see Ans. 25–29) differs to some Appeal 2019-003234 Application 15/004,646 13 extent from our analysis and findings above, particularly with respect to FF3–4. Accordingly, we designate our affirmance a new ground of rejection under 37 C.F.R. § 41.50(b) in order to provide Appellant an opportunity to fully respond to these issues. III. OBVIOUSNESS REJECTIONS INVOLVING CURSIEFEN AND BACHMANN Issue Rejections III and IV are premised on the common application of Cursiefen or Bachmann in combination with either Cao or Bzowska. See Final Act. 23–26. Because these rejections involve common issues and arguments, we analyze them together. The issue for each rejection is whether the preponderance of evidence of record supports Examiner’s conclusion that the cited prior art renders Appellant’s claimed method obvious. Findings of Fact FF8. Cursiefen teaches that “[i]nhibition of hem- and lymphangiogenesis (afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival.” Cursiefen, 2666. Cursiefen describes experiments in which a VEGF-A trap was administered either at or after the time of corneal transplant surgery in mice. See generally id. at 2667–70. Cursiefen reports that administration of the VEGF-A trap inhibited both LG and HG (id. at 2669–70) and “significantly improved long-term graft survival at 8 weeks after surgery” as compared to control (id. at 2671 (Fig. 5)). Cursiefen teaches that these results “establish hem- and lymphangiogenesis occurring after normal-risk keratoplasty as novel risk factors for subsequent immune rejections. Id. at 2671. Appeal 2019-003234 Application 15/004,646 14 FF9. Bachmann describes experiments in which a VEGF-A trap was administered either at or after the time of surgery in a high-risk corneal transplantation mouse model. Bachmann, 71. Bachmann reports that “[n]euralization of VEGF-A after high-risk corneal transplantation effectively inhibits postoperative hemangiogenesis, lymphangiogenesis, and recruitment of antigen-presenting cells and improves corneal graft survival.” Id. Bachmann teaches that “temporarily inhibiting post-operative hemangiogenesis and lymphangiogenesis promotes graft survival, even after high-risk transplantation.” Id. at 72. FF10. Cao describes experiments “[t]o evaluate the role of angiopoietin-2 (Ang2) in corneal angiogenesis . . . following injury” involving subcutaneous administration of an Ang-2 antibody that binds and neutralizes Ang-2 “on days 0, 3 and 6 following injury.” Cao, 1. Cao teaches that both choroidal neovascularization and “growth of lymphatic vessels into the injured cornea were significantly decreased by anti-Ang2 treatment.” Id. Analysis Examiner finds that both Cursiefen and Bachmann teach a method of treating corneal transplant rejection involving administration of an agent to inhibit HG and LG and the transplantation of corneal tissue into a graft bed. See Final Act. 23–24. Examiner determines it would have been obvious to substitute the anti-Ang2 antibody of Cao (Rejection III) or the anti-Ang2 antibody of Bzowska (Rejection IV) for the VEGF-A trap used in Cursiefen and Bachmann because “like the compounds taught in Cursiefen et al and Bachmann et al, anti-Ang2 antibodies inhibit both hem- and lymphangiogenesis” and “[s]ubstituting a known element for another, to Appeal 2019-003234 Application 15/004,646 15 yield the known result, is obvious.” Id. at 24, 26 (citing KSR Int’l v. Teleflex, Inc., 550 U.S. 398, 416 (2007)). We adopt Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 24–28; FF7–10) and agree that claims 44–46, 50–52, and 56 are rendered obvious by the prior art cited in Rejections III and IV. We address Appellant’s arguments below. Appellant argues that “[o]ne of ordinary skill in the art would not modify the method of Cursiefen or Bachmann to use” the “anti-Ang-2 antibody” taught in Cao or Bzowska “because the art [i.e., Dietrich] teaches anti-Ang-2 antibodies have an unsuitable activity [i.e., inhibiting HG] that could have an adverse effect on such methods.” Appeal Br. 23, 28. We disagree for several reasons. First, Appellant’s argument ignores the fact that both Cursiefen and Bachmann specifically teach that inhibition of both LG and HG promotes corneal graft survival. FF8–9. Appellant has not articulated why one of skill in the art would disregard the express teachings in Cursiefen and Bachmann. Second, as explained above, we disagree with Appellant’s interpretation of Dietrich. Dietrich teaches that LG is the “most important mediator of immune rejections after corneal transplantation,” but it does not teach that LG is only such mediator. FF2. Rather, Dietrich teaches that inhibiting both LG and HG promotes corneal graft survival. FF3. Thus, Dietrich is consistent with Cursiefen and Bachmann in teaching that corneal graft rejection can be treated by administering an agent that inhibits both LG and HG. Both Cao (FF10) and Bzowska (FF7) teach that Ang-2 neutralizing antibodies inhibit LG and HG. Appeal 2019-003234 Application 15/004,646 16 Third, contrary to what is implied by Appellant’s arguments, Appellant’s claims do not require selective or preferential inhibition of LG over HG. As explained in our analysis of the Written Description Rejection, all claim 44 requires is the administration of an antibody that antagonizes the Ang-2 ligand at the Tie-2 receptor in an amount effective to treat the subject for corneal transplant rejection. The cited prior art discloses such antibodies. Indeed, Bzowska discloses the same exemplary anti-Ang-2 antibodies (i.e., MEDI3617 and LC06) identified in the Specification (see Spec. 15, 15–18) and teaches they exhibit antiagiogenic action by antagonizing binding of Ang-2 to the Tie-2 receptor. FF7. Moreover, the teachings in the other references are sufficient to provide at least a reasonable expectation that such anti-Ang-2 antibodies will be effective to treat corneal transplant rejection. See FF8–10. We are likewise unpersuaded by Appellant’s unexpected results arguments. See Appeal Br. 25–26, 30–31. Appellant advances the same arguments premised on the results in Examples 1 and 2 of the Specification that it did for the other obviousness Rejection II. Id. Those arguments are not persuasive for the same reasons explained above. In addition, both Cursiefen and Bachmann teach that inhibiting LG and HG improves corneal graft survival (FF8–9) and Cao teaches that corneal LG can be inhibited by administration of an anti-Ang-2 antibody (FF10). These teachings further demonstrate that the results in Examples 1 and 2 of the Specification would have been expected to one of ordinary skill in the art in view of the prior art. See In re Gershon, 372 F.2d at 537. When considered in context of the record as a whole, Appellant’s evidence does not overcome Examiner’s prima facie showing. Accordingly, Appeal 2019-003234 Application 15/004,646 17 we affirm the rejection of claim 44. We affirm the rejection of claims 45, 46, 50–52, and 56, which are not argued separately, for the same reasons. See 37 C.F.R. § 41.37(c)(1)(iv). CONCLUSION For the reasons explained above, we determine the preponderance of the evidence does not support the Written Description Rejection. We affirm Rejection II, but enter our affirmance as a new ground of rejection. We determine that Rejections III and IV are supported by the preponderance of the evidence and therefore affirm. DECISION SUMMARY Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed New Ground 44–46, 50–52, 56 112(a) Written Description 44–46, 50–52, 56 44–46, 50–52, 56 103 Dietrich, Chen, Holopainen, Bzowska 44–46, 50–52, 56 44–46, 50–52, 56 44–46, 50–52, 56 103 Cursiefen, Bachmann, Cao 44–46, 50–52, 56 44–46, 50–52, 56 103 Cursiefen, Bachmann, Bzowska 44–46, 50–52, 56 Overall Outcome 44–46, 50–52, 56 44–46, 50–52, 56 FINALITY AND RESPONSE This decision contains a new ground of rejection pursuant to 37 C.F.R. § 41.50(b). 37 C.F.R. § 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review.” 37 C.F.R. § 41.50(b) also provides that the Appellant, WITHIN TWO Appeal 2019-003234 Application 15/004,646 18 MONTHS FROM THE DATE OF THE DECISION, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new evidence relating to the claims so rejected, or both, and have the matter reconsidered by the examiner, in which event the prosecution will be remanded to the examiner. . . . (2) Request rehearing. Request that the proceeding be reheard under § 41.52 by the Board upon the same record. . . . AFFIRMED; 37 C.F.R. § 41.50(b) Copy with citationCopy as parenthetical citation